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Transition-State Theory and Reaction Mechanism in Drug Action and Drug Design

  • James K. Coward

Abstract

Rational development of potent and specific new drugs requires a detailed knowledge of the chemical mechanism of action for available pharmacologic agents and/or the enzymes which catalyze a drug-sensitive reaction. Numerous drugs now in the pharmacopeia have been discovered largely by serendipity and by testing thousands of analogs of known effective agents. However, the emergence of bioorganic chemistry has provided a mechanistic foundation on which medicinal chemists and pharmacologists can construct a detailed understanding of the mode of action of drugs currently available and can improve the design of new agents. In previous chapters of this book, others have presented detailed descriptions of the determination of transition-state structures and their role in biochemical reactions. In this chapter, the application of these concepts to understanding the mode of drug action and to the design of new drugs will be considered. The use of transition-state analogs and multisubstrate adducts as potent and specific chemotherapeutic agents (the theoretical aspects of which were described by Wolfenden in Chapter 15) will be presented as the logical extension of transition-state theory into pharmacology. The preceding chapters have dealt with phenomena for which there is a considerable amount of literature available. In this final chapter, we shall discuss an approach to the study of drug action and drug design about which there is very little in the literature. It is hoped that this brief presentation will stimulate others to attempt to bridge the gap between bioorganic chemistry and pharmacology.

Keywords

Drug Design Dihydrofolate Reductase Thymidylate Synthetase Carbamyl Phosphate Aspartate Transcarbamylase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    L. S. Goodman and A. Gilman, eds., The Pharmacological Basis of Therapeutics, 5th ed., Macmillan, New York (1975).Google Scholar
  2. 2.
    A. Goldstein, L. Aronow, and S. M. Kalman, eds., Principles of Drug Action, 2nd ed., Wiley, New York (1974).Google Scholar
  3. 3.
    H. P. Rang, ed., Drug Receptors, University Park Press, Baltimore (1973).Google Scholar
  4. 4.
    A. Albert, Selective Toxicity; the Physico-Chemical Basis of Therapy, 5th ed., Chapman & Hall, London (1973).Google Scholar
  5. 5.
    R. J. Suhadolnik, Nucleoside Antibiotics, Wiley-lnterscience, New York (1970).Google Scholar
  6. 6.
    D. V. Santi and Charles S. McHenry, 5-Fluoro-2’-deoxyuridylate: Covalent complex with thymidylate synthetase, Proc. Nat. Acad. Sci. USA 69, 1855–1857 (1972).PubMedCrossRefGoogle Scholar
  7. 7.
    D. V. Santi, C. S. McHenry, and H. Sommer, Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylate, Biochemistry 13, 471–481 (1974).PubMedCrossRefGoogle Scholar
  8. 8.
    R. J. Langenback, P. V. Danenberg, and C. Heidelberger, Thymidylate synthetase: Mechanism of inhibition by 5-fluoro-2’-deoxyuridylate, Biochem. Biophys. Res. Commun. 48, 1565–1571 (1972).CrossRefGoogle Scholar
  9. 9.
    P. V. Danenhcrg, R. J. Langenback, and C. Heidelberger, Structures of reversible and irreversible complexes of thymidylate synthetase and fluorinated pyrimidine nucleotides, Biochemistry 13, 926–933 (1974).CrossRefGoogle Scholar
  10. 10.
    A. L. Pogolotti, Jr., and D. V. Santi, Model studies of the thymidylate synthetase reaction. Nucleophilic displacement of 5-p-nitrophenoxymethyluracils, Biochemistry 13, 456–466 (1974), and references therein.CrossRefGoogle Scholar
  11. 11.
    Y. Wataya and D. V. Santi, Thymidylate synthetase catalyzed dehalogenation of 5-bromoand 5-iodo-2’-deoxyuridylate, Biochem. Biophys. Res. Commun. 67, 818–823 (1975).PubMedCrossRefGoogle Scholar
  12. 12.
    T. I. Kalman, Glutathione-catalyzed hydrogen isotope exchange of position 5 of uridine. A model for enzymic carbon alkylation reactions of pyrimidines, Biochemistry 10, 2567–2573(1971); Inhibition of thymidylate synthetase by showdomycin and its 5’-phosphate, Biochem. Biophys. Res. Commun. 49, 1007–1013 (1972).PubMedCrossRefGoogle Scholar
  13. 13.
    a) C. S. McHe.nry and D. V. Santi, A sulfhydryl group is not the covalent catalyst in the thymidylate synthetase reaction, Biochem. Biophys. Res. Commun. 57, 204–208 (1974). (b) H. Sommer and D. V. Santi, Purification and amino acid analysis of an active site peptide from thymidylate synthetase containing covalently bound 5-fluoro-2’-deoxyuridylate and methylenetetrahydrofolate, Biochem. Biophys. Res. Commun. 57, 689–695 (1974). (e) R. L. Bellisario, G. F. Maley, J. H. Galivan, and F. Maley, Amino acid sequence at the FdUMP binding site of thymidylate synthetase, Proc. Natl. Acad. Sci. U.S.A. 73, 1848–1852 (1952).Google Scholar
  14. 14.
    W. C. Werkheiser, Specific binding of 4-amino folic acid analogues by folic acid reductase, J. Biol. Chem. 236, 888–893 (1961).Google Scholar
  15. 15.
    J. R. Bertino, B. A. Booth, A. L. Bieber, A. Cashmore, and A. C. Sartorelli, Studies on the inhibition of dihydrofolate reductase by the folate antagonists, J. Biol. Chem. 239, 479–485 (1964).PubMedGoogle Scholar
  16. 16.
    fPoe, N. J. Greenfield, J. M. Hirshfield, and K. Hoogsteen, Dihydrofolate reductase from a methotrexate-resistant strain of Escherichia coli: Binding of several folates and pteridines as monitored by ultraviolet difference spectroscopy, Cancer Biochem. Biophys. 1, 7–11 (1974).Google Scholar
  17. 17.
    R. Wolfenden, Analog approaches to the structure of the transition state in enzyme reactions, Acc. Chem. Res. 5, 10–18 (1972).CrossRefGoogle Scholar
  18. 18.
    R. Wolfenden, Analog inhibitors and enzyme catalysis, Annu. Rev. Biophys. Bioeng. 5, 271–305 (1976).PubMedCrossRefGoogle Scholar
  19. 19.
    K. D. Collins and G. R. Stark, Aspartate transcarbamylase. Interaction with the transition state analogue N-(phosphonacetyi)-L-aspartate, J. Biol. Chem. 246, 6599–6605 (1971).PubMedGoogle Scholar
  20. 20.
    E. A. Swyryd, S. A. Seaver, and G. R. Stark, N-(Phosphonacetyl)-L-aspartate, a potent transition state analog inhibitor of aspartate transcarbamylase, blocks proliferation of mammalian cells in culture, J. Biol. Chem. 249, 6945–6950 (1974).PubMedGoogle Scholar
  21. 21.
    T. Yoshida, G. R. Stark, and N. J. Hoogenraad, Inhibition by N-(phosphonacetyl)-L-aspartate of aspartate transcarbamylase activity and drug-induced cell proliferation in mice, J. Biol. Chem. 249, 6951–6955 (1974).PubMedGoogle Scholar
  22. 22.
    G. R. Jacobson and G. R. Stark, in: The Enzymes, 3rd ed. (P. D. Boyer, ed.), Vol. IX, pp. 226–308, Academic Press, New York (1973).Google Scholar
  23. 23.
    N. J. Hoogenraad, Reaction mechanism of aspartate transcarbamylase from mouse spleen, Arch. Biochem. Biophys. 161, 76–82 (1974).CrossRefGoogle Scholar
  24. 24.
    K. Schray and J. P. Klinman, The magnitude of enzyme transition state analog binding constants, Bioehern. Biophys. Res. Commun. 57, 641–648 (1974).CrossRefGoogle Scholar
  25. 25.
    J. S. Heller, E. S. Canellakis, D. L. Bussolotti, and J. K. Coward, Stable multisubstrate adducts as enzyme inhibitors. Potent inhibition of ornithine decarboxylase by N-(S’-phosphopyridoxyl)ornithine, Biochim. Biophys. Acta 403, 197–207 (1975).PubMedCrossRefGoogle Scholar
  26. 26.
    J. S. Heller, N. C. Motola, J. K. Coward, and E. S. Canellakis, unpublished results.Google Scholar
  27. 27.
    M. Robert-Gero, F. Lawrence, and P. Vigier, Inhibition by methioninyl adenylate of focus formation by rous sarcoma virus, Cancer Res 35 3571–3576 (1975), and references thereinPubMedGoogle Scholar
  28. 28.
    C. Borri Voltattorni, A. Orlacchio, A. Giartosio, F. Conti, and C. Turano, The binding of coenzymes and analogues to the substrate—coenzyme complex to tyrosine aminotransferase, Eur. J. Biochem. 53, 151–160 (1975).CrossRefGoogle Scholar
  29. 29.
    E. S. Severin, N. N. Gulyaev, E. N. Khurs, and R. M. Khomutov, The synthesis and properties of phosphopyridoxyl amino acids, Biochem. Biophys. Res. Commun. 35, 318–323 (1969).PubMedCrossRefGoogle Scholar
  30. 30.
    C. Born Voltattorni, A. Minelli, and C. Turano, Boll. Soc. ltal. Bin!. Spec. 47. 700&702 (1971).Google Scholar
  31. 31.
    R. T. Borchardt, in: The Biochemistry of S-Adenosylmethionine (F. Salvatore and E. Borek, eds.), Columbia University Press, New York in press.Google Scholar
  32. 32.
    J. K. Coward, D. L. Bussolotti, and C.-D. Chang, Analogs of S-adenosylhomocysteine as potential inhibitors of biological transmethylation. Inhibition of several methylases by Stubercidinylhomocysteine, J. Med. Chem. 17, 1286–1289 (1974).PubMedCrossRefGoogle Scholar
  33. 33.
    C.-D. Chang and J. K. Coward, Effect of S-adenosylhomocysteine and S-tubercidinylhomo-cysteine on transfer ribonucleic acid methylation in phytohemagglutinin-stimulated lymphocytes, Mol. Pharmacol. 11, 701–707 (1975).PubMedGoogle Scholar
  34. 34.
    R. J. Michelot, N. Lesko, R. W. Stout, and J. K. Coward, Effect of S-adenosylhomocysteine and S-tubercidinylhomocysteine on catecholamine methylation in neuroblastoma cells, Mol. Pharmacol. 13, 368–373 (1977).PubMedGoogle Scholar
  35. 35.
    P-J. Cheng, W. D. Nunn, R. J. Tyhach, S. L. Goldstein, R. Engel, and B. E. Trapp, Investigations concerning the mode of action of 3,4-dihydroxybutyl-l-phosphonate on Escherichia coli. In vitro examination of enzymes involved in glycerol 3-phosphate metabolism, J. Biol. Chem. 250 1633–1639 (1975).Google Scholar
  36. 36.
    G. Goring and F. Cramer, Synthese von Inhibitoren für die Phenylalanyl-tRNA-Synthetase: Methylen-Analoge des Phenylalanyl-adenylats, Chem. Ber. 106, 2460–2467 (1973).CrossRefGoogle Scholar
  37. 37.
    J. Uren and P. K. Chang, personal communication.Google Scholar
  38. 38.
    J. Frank Henderson and A. R. P. Paterson, Nucleotide Metabolism, Academic Press, New York (1973).Google Scholar
  39. 39.
    R. D. Walker and J. A. Duerre, S-Adenosylhomocysteine metabolism in various species, Can. J. Biochem. 53, 312–319 (1975).PubMedCrossRefGoogle Scholar
  40. 40.
    C.-D. Chang and J. K. Coward, Analogues of S-adenosylhomocysteine as potential inhibitors of biological transmethylation. Synthesis of analogues with modifications at the 5’-thioether linkage, J. Med. Chem. 19, 684–691 (1976).PubMedCrossRefGoogle Scholar
  41. 41.
    J. K. Coward, N. C. Motola, and J. D. Moyer, Polyamine biosynthesis in rat prostate. Substrate and inhibitor properties of 7-deaza analogues of decarboxylated S-adenosylmethionine and 5’-methylthioadenosine, J. Med. Chem. 20, 500–505 (1977).PubMedCrossRefGoogle Scholar
  42. 42.
    A. A. Sinkula, The prodrug approach in drug design, Annu. Rep. Med. Chem. 10, 306–316 (1975).CrossRefGoogle Scholar
  43. 43.
    R. Hirschmann, R. G. Strachan, P. Buchschacher, L. H. Sarrett, S. L. Steelman, and R. Silber, An approach to an improved antiinflammatory steroid. The synthesis of 1lß,17-dihydroxy3,20-dione-l,4-pregnadien-21-y1 2-adetamido-2-deoxy-ß-D-glucopyranoside, J. Am. Chem. Soc. 86, 3903–3904 (1964).CrossRefGoogle Scholar
  44. 44.
    N. Bodor, E. Shek, and T. Higuchi, Delivery of a quaternary pyridinium salt across the blood-brain barrier by its dihydropyridine derivative, Science 190, 155–156 (1975).PubMedCrossRefGoogle Scholar
  45. 45.
    a) N. Bodor, E. Shek, and T. Higuchi, Improved delivery through biological membranes. 1. Synthesis and properties of 1-methyl-1,6-dihydropyridine-2-carbaldoxime, a pro-drug of N-methylpyridinium-2-carbaldoxime chloride, J. Med. Chem. 19, 102–107 (1976). (b) E. Shek, T. Higuchi, and N. Bodor, Improved delivery through biological membranes. 2. Distribution, excretion, and metabolism of N-methyl-1,6-dihydropyridine-2-carbaldoxime hydrochloride, a pro-drug of N-methylpyridinium-2-carbaldoxime chloride, J. Med. Chem. 19, 108–112 (1976). (c) E. Shek, T. Higuchi, and N. Bodor, Improved delivery through biological membranes. 3. Delivery of N-methylpyridinium-2-carbaldoxime chloride through the blood-brain barrier in its dihydropyridine pro-drug form, J. Med. Chem. 19, 113–117 (1976).PubMedCrossRefGoogle Scholar
  46. 46.
    T.L. Rosenberry, Acetylcholinesterase, Adv. Enzymol 43 103–218 (1975).Google Scholar
  47. 47.
    R. H. Abeles and A. L. Maycock, Suicide enzyme inactivators, Ace. Chem. Res. 9, 313–319 (1976).CrossRefGoogle Scholar
  48. 48.
    R. R. Rando, Chemistry and enzymology of kcal inhibitors, Science 185, 320–324 (1974).PubMedCrossRefGoogle Scholar
  49. 49.
    R. R. Rando, Mechanisms of action of naturally occurring irreversible enzyme inhibitors, Acc. Chem. Res. 8, 281–288 (1975).CrossRefGoogle Scholar
  50. 50.
    R. R. Rando, Commentary on the mechanism of action of antibiotics which act as irreversible enzyme inhibitors, Biochem. Pharmacol. 24, 1153–1160 (1975).PubMedCrossRefGoogle Scholar
  51. 51.
    K. Endo, G. M. Helmkamp, and K. Block, Mode of inhibition of ß-hydroxydecanoyl thioester dehydrase by 3-decynoyl-N-acetylcysteamine, J. Biol. Chem. 245, 4293–4296 (1970).PubMedGoogle Scholar
  52. 52.
    G. M. Helmkamp, R. R. Rando, D. J. H. Brock, and K. Block, ß-Hydroxydecanoyl thioester dehydrase. Specificity of substrates and acetylenic inhibitors, J. Biol. Chem. 243, 3229–3231 (1968).PubMedGoogle Scholar
  53. 53.
    L. R. Kass, The antibacterial activity of 3-decynoyl-N-acetylcysteamine, J. Biol. Chem. 243, 3223–3228 (1968).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1978

Authors and Affiliations

  • James K. Coward
    • 1
  1. 1.Department of PharmacologyYale University School of MedicineNew HavenUSA

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